Process for the racemization of 1-benzyl-4-(4-fluorophenyl)-3-hydroxymethyl-1,2-3,6-tetrahydropyridine to be used as intermediate in the synthesis of paroxetine

ABSTRACT

A process for the racemization of enantiomerically enriched 1-benzyl-4-(4-fluorophenyl)-3-hydroxymethyl-1,2,3,6-tetrahydropyridine which is a useful intermediate in the preparation of paroxetine. Formula (A) means that the compound (I) has an enantiomeric excess of one enantiomer over the other enantiomer. R 1  and R 2  are defined as in claim  1.

This application is a 371 of PCT/EP01/09998, filed Aug. 30, 2001, andclaims priority to GB0021147.4, filed Aug. 30, 2000.

This invention relates to a process for the racemisation ofenatiomerically enriched1-benzyl-4-(4-fluorophenyl)-3-hydroxy-methyl-1,2,3,6-tetrahydropyridinewhich is a useful intermediate in the preparation of paroxetine.

U.S. Pat. No. 4,007,196 discloses compounds which possessanti-depressant activity. One particular compound disclosed in thispatent is known as paroxetine and has the structure A below:

This compound has been found to be especially useful in the treatment ofdepression and several processes have been described to prepare thisimportant compound. WO 96/36636 (which is incorporated herein byreference) discloses one such process. WO 98/52920 (which isincorporated herein by reference) discloses a process for preparing auseful intermediate in the preparation of paroxetine.

WO 98/01424 (which is incorporated herein by reference) discloses aprocess for the preparation of racemictrans-1-benzyl-3-hydroxymethyl-4-(4-fluorophenyl)piperidine in which4-(4-fluoro-phenyl)-N-benzyl-1,2,5,6-tetrahydropyridine is reacted withformaldehyde in acidic medium via the Prins reaction to give the desiredproduct. One of the optional next stages for the process is theresolution of this compound with an optically active acid, preferablydibenzoyltartaric acid ordi-p-toluyl-tartaric acid, to give theindividual enantiomers oftrans-1-benzyl-3-hydroxymethyl-4-(4-fluorophenyl)piperidine. Clearlythis process is wasteful in that 50% of the material is then discardedas only one enantiomer, the (+)-enantiomer, is further processed to giveparoxetine. It would be desirable to be able to racemise the unwantedenantiomer and to then resolve the racemic mixture to produce more ofthe desired enantiomer. However, many attempts by the present applicantsto find a satisfactory racemisation process ended in failure.

Surprisingly an efficient process for carrying out this racemisation hasnow been found.

The present invention provides a process for the racemisation of acompound of formula I comprising the steps of

-   a) reacting an enantiomerically enriched compound of formula I-    in which R₁ represents an amine protecting group, with a compound    of formula II    R₂X  II-    in which R₂ represents a group of formula R₃SO₅—in which R₃    represents optionally substituted phenyl, a C₁₋₆alkyl group or a    trifluoromethyl group and X represents halo to give a compound of    formula III-    in which i) R₂ represents a group of formula R₃SO₂—in which R₃    represents optionally substituted phenyl, a C₁₋₆alkyl group or a    trifluoromethyl group,-   b) reacting the compound of formula III with a compound of formula    IV-    in which M represents an alkali metal and R represents H, a    C₁₋₆alkyl group, optionally substituted phenyl or an (optionally    substituted phenyl)hydroxyC₁₋₆alkyl group to give a substantially    racemic compound of formula V-    in which R₁ and R are as previously defined; and-   c) reacting the compound of formula V with a hydrolysing agent to    give a substantially racemic compound of formula I.

It will be appreciated by those skilled in the art that the compounds offormula III may also be prepared by reacting a compound of formula Iwith an halogenating agent to give a compound of formula Ia

in which Y is halo. The compound of formula Ia may then be reacted witha salt of formula MOR₂ in which R₂ is as previously defined to give acompound of formula III. This alternative process also forms part of thepresent invention.

Suitably halogenating agents include hydrogen bromide, hydrogenchloride, oxalyl chloride, phosphorus pentachloride, phosphorustrichloride, phosphorus pentabromide, phosphorus tribromide, bromine,phosphorus oxychloride, phosphorus oxybromide, thionyl chloride, thionylbromide, a mixture of carbon tetrachloride and triphenylphosphine, amixture of tetrabromomethane and triphenyl-phosphine, N-bromosuccinimideand N-chlorosuccinimide. Preferably the halogenating agent is thionylchloride or thionyl bromide.

Whilst not bound by theory, it is believed that the mechanism of theabove racemisation process involves an intermediate salt which is acompound of formula IIIa

in which R₁ is as previously and R₂ ⁻ is an anion of formula R₃SO₂ ⁻.The compound of formula IIIa in which R₂ ⁻ represents the anion ⁻OSO₂CF₃and R₁ represents benzyl has been isolated from the reaction mixture andidentified. In addition the product of formula IIIa where R₂ ⁻represents ⁻OSO₂-Ph has been identified in the reaction solution bynuclear magnetic resonance spectroscopy.

In a preferred aspect the present invention provides a process for theracemisation of a compound of formula I comprising the steps of

-   a) reacting an enantiomerically enriched compound of formula I-    in which R₁ represents an amine protecting group, with a compound    of formula II    R₂X  II-    in which R₂ represents a group of formula R₃SO₂—in which R₃    represents optionally substituted phenyl, a C₁₋₆alkyl group or a    trifluoromethyl group and X represents halo to give a compound of    formula III-    in which i) R₂ represents a group of formula R₃SO₂—in which R₃    represents optionally substituted phenyl, a C₁₋₆alkyl group or a    trifluoromethyl group, wherein the compound of formula III is in    equilibrium with a compound of formula IIIa-    in which R₁ represents an amine protecting group and R₂—is an anion    of R₂-   b) reacting the compound of formula IIIa with a compound of formula    IV-    in which M represents an alkali metal and R represents H, a    C₁₋₆alkyl group, optionally substituted phenyl or an (optionally    substituted phenyl)hydroxyC₁₋₆alkyl group to give a substantially    racemic compound of formula V-    in which R₁ and R are as previously defined; and-   c) reacting the compound of formula V with a hydrolysing agent to    give a substantially racemic compound of formula I.

In a further aspect the present invention provides compounds of formulaIIIa

in which R₁ represents an amine protecting group and R₂ is a previouslystated. Preferably R₁ represents benzyl or a C₁₋₆-alkyl group. Morepreferably R₁ represents benzyl, methyl or ethyl. Most preferably R₁represents benzyl. Preferably R₂ ⁻ is a benzene-sulphonate anion, amethanesulphonate anion or a trifluoro-methanesulphonate anion.

Preferably the amino protecting group is one which is inert to reductionby a metal hydride. More preferably the amine protecting group isselected from a) allyl, b) benzhydryl, c) methoxymethyl, d)benzyloxymethyl, e) tetrahydropyranyl, f) an optionally substitutedbenzyl group, g) di(p-methoxy-phenyl)methyl, h) triphenylmethyl, i)(p-methoxyphenyl)diphenyl-methyl, j) diphenyl-4-pyridylmethyl, k) aC₁₋₆alkyl group, for example methyl or ethyl, 1) a trifluoro C₁₋₄alkylgroup, m) an alkynyl group or n) p-methoxybenzyl. Most preferably theamine protecting group is a benzyl group which is optionally substitutedon the phenyl ring by one or more of the following groups: a C₁₋₄alkylgroup, a C₁₋₄alkoxy group, halo or nitro. Especially preferably R₁represents benzyl.

The term optionally substituted phenyl means phenyl substituted by oneor more of the following: a) a C₁₋₆alkyl group, b) nitro or c) halo.

The term enantiomerically enriched should be understood to mean that thecompound of formula I has an enantiomeric excess of one enantiomer overthe other enantiomer in the range of 1 to 100%, preferably anenantiomeric excess in the range of 50 to 100%, and more preferably anenantiomeric excess in the range of 70 to 100%.

Suitably either enantiomer may predominate in the enantiomericallyenriched compound. Preferably the predominant enantiomer is the (+)enantiomer. More preferably the predominant enantiomer is the(−)enantiomer.

The term substantially racemic means that there is an enantiomericexcess of less than 20% preferably less than 10% and most preferablyless than 5%.

Preferably R₃ represents methyl or phenyl optionally substituted by amethyl group, a nitro group or halo. More preferably R₃ representsmethyl, 4-tolyl, 4-nitrophenyl, or 4-bromophenyl.

Suitably the hydrolysing agent includes a basic or acidic hydrolysingagent. Preferred basic hydrolysing agents include aqueous sodiumhydroxide, aqueous ammonia, aqueous potassium carbonate, aqueouspotassium bicarbonate, aqueous sodium bicarbonate, aqueous sodiumcarbonate, potassium hydroxide, aqueous potassium hydroxide and aqueouslithium hydroxide. Preferred acidic hydrolysing agents includehydrochlorid acid, hydrobromic acid and sulphuric acid. Most preferablythe hydrolysing agent is aqueous hydrochloric acid or aqueous sodiumhydroxide solution.

In another aspect the present invention provides novel compounds offormula III and V in which R₁ and R are as previously defined which areuseful as intermediates in the preparation of paroxetine. Preferably R₁is benzyl. Preferably R is methyl. Preferably M is potassium.

In yet another aspect the present invention provides a process for thepreparation of paroxetine from a compound of formula I according to themethods described in WO 96/36636, and WO 98/01424 characterised in thatthe compound of formula I was prepared by racemisation of anenantiomerically enriched compound of formula I by the process of thepresent invention. The paroxetine may be obtained as the hydrochloridesalt as the anhydrous form or the hemihydrate or other solvate. Theprocess of the present invention may also be used in conjunction withthe process described in WO 98/52920 to prepare an intermediate whichmay be further processed as described below to produce paroxetine. Thesecombination processes also form part of the present invention.

The process of the present invention is advantageous because it providesa pure precursor to paroxetine. Paroxetine may be obtained in a pureform from compounds of formula I by a) conversion of the hydroxy groupinto a leaving group, for example halo or tosyloxy, b) reaction withsesamol or a salt thereof, c) removal of the protecting group R₁ byconventional means for example by hydrogenolysis when R₁ is benzyl andoptionally d) salt formation, for example the hydrochloride salt as theanhydrous form or the hemihydrate.

The invention is illustrated by the following Examples which are givenby way of example only. The final product of each of these Examples wascharacterised by one or more of the following procedures: gas-liquidchromatography: high performance liquid chromatography: elementalanalysis; nuclear magnetic resonance spectroscopy and infraredspectroscopy.

EXAMPLES Example 1

Triethylamine (3.2 ml) was added to a solution of(+)-benzyl-3-hydroxymethyl-4-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine(21.7 g) in dichlormethan (87 ml) at ambient temperature and thenbenzenesulphonyl chloride (11.3 ml) was added to the solution withstirring. The mixyture was stirred at ambient temperature for 18 hours.Water (b74 ml) was added and the mixture was stirred for 10 minutes. Theorganic layer was separated off, washed with water (74 ml), then dried,filtered and evaporated to give (+)-1-benzyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-3-methyl benzenesulphonate.

Example 2

Potassium acetate (1.23 g) was added to a stirred solution of(+)-1-benzyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-3-methylbenzenesulphonate (5.0 g) in acetonitrile (50 ml). 18-Crown-6 (0.3 g)was added to the mixture and the mixture was stirred at ambienttemperature for 18 hours and then stirred and boiled under reflux 6hours. The mixture was allowed to cool to ambient temperature and thenallowed to stand at this temperature for 64 hours. Water (50 ml) wasadded, followed by ethyl acetate (50 ml). The mixture was stirred foraround 5 minutes. TYhe organic layer was separated, washed with water(50 ml), dried, filtered and evaporated to give (+,−)-1-benzyl-4-(4-fluorophenyl)-1, 2, 3, 6-tetrehydropyridine-3-methyl acetate.

Example 3

Aqueous sodium hydroxide solution (1.84 ml of a 4M solution) was addedto a solution of (+,−)-1-benzyl-4-(4-fluorophenyl)-1, 2, 3,6-tetrahydropyridine-3-methyl acetate (0.5 g) in industrial methylatedspirits (5 ml). The mixture was boiled under reflux for 4.25 hours. Themixture was evaporated under reduced pressure and then water (10 ml) andtoulene (10 ml) were added to the residue. The organic layer wasseparated, washed with water (10 ml) then dried, filtered and evaporatedto give (+,−)-1-benzyl-3-hydroxymethyl -4-(4-fluorophenyl)-1, 2, 3,6-tetrahydropyridine (ee 11.6%).

Example 4

Triethylamine (3.2 ml) was added to a solution of(+)-1-benzyl-3-hydroxymethyl-4-(4-fluorophenyl)-1, 2, 3,6-tetrahydropyridine (5.65 g) in toluene (44.35 g) and the mixture wasstirred at ambient temperature. The solution was cooled to 5°C. in anice/water bath and the methanesulphonyl chloride (1.6 ml) was addeddropwise over a minute. The temperature rose to 11°C. over 5 minutes andthen dropped to 5°C. over 5 minutes. The mixture was stirred at 0-5°C.for 75 minutes. The mixture was allowed to warm to 10°C. and water (10ml) was added. The mixture was stirred for 5 minutes and then theorganic layer was separated, washed with water (20 ml), and then dried,filtered and evaporated to give (+)-1-benzyl-4-(4-fluorophenyl) -1, 2,3, 6-tretrahydropyridine-3-methyl methanesulphonate as an oil whichsolidified on standing. [α]_(D)21.5°C.=+78.2 ±1.4]concentration 2.0735 gper 100 ml of chloroform.

Example 5

Potassium acetate (1.23 g) and 18-crown-6 (0.3 g) were added to astirred solution of(+)-1-benzyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-3-methylmethanesulphonate (4.27 g) in acetonitrile (50 ml) with stirring, Themixture was stirred at ambient temperature for 1.5 hours and then boiledunder reflux with scirring for 5 hours, The mixture was allowed to standat ambient temperature for 64 hours and then boiling under reflux wascontinued for a further 5 hours. The mixture was cooled to ambienttemperature and then ethyl acetate (50 ml) and water (50 ml) were added.The mixture was stirred for approximately 5 minutes and then brine (20ml) was added to the mixture followed by dry ethyl acetate (10 ml). Theorganic layer was separated, washed with brine (50 ml), dried, filteredand evaporated to give(+,−)-1-benzyl-4-(4-fluorophenyl-1,2,3,6-tetrahydropyridine-3-methylacetate.

Example 6

Aqueous sodium hydroxide solution (9.6 ml of a 4M solution) was added toa solution of(+,−)-1-benzyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-3-methylacetate (2.6 g) in industrial methylated spirits (26 ml) with stirring.The mixture was boiled under reflux for 1.5 hours. The mixture wasevaporated under reduced pressure and then toluene (40 ml) and water (20ml) were added. The organic layer was removed, washed with water, andthen dried, filtered and evaporated to give(+,−)-1-benzyl-3-hydroxy-methyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine(ee 16.3%).

Example 7

A solution of(−)-enriched)-1-benzyl-3-hydroxymethyl-4-(4-fluoro-phenyl)-1,2,3,6-tetrahydropyridine(19.8 g) in toluene (100 g) which had been previously dried byazeotropic distillation, was stirred at ambient temperature whilsttriehylamine (13.9 ml) and benzenesulphonyl chloride (9.9 ml) wereadded. The mixture was stirred at ambient temperature for 64 hours.Water (64 ml) was added and the mixture was stirred for approximately 15minutes. The organic layer was separated off, washed with water and asample (10 ml) was removed for analysis. The remaining toluene solutionwas boiled under reflux with azeotropic removal of the water using aDean & Stark apparatus for approximately 15 minutes. The mixture wascooled to ambient temperature and potassium acetate (7.18 g) andpropan-2-ol (97.2 ml) were added. The mixture was boiled under refluxfor 19 hours, then cooled to 45° C. and ah aqueous solution of sodiumhydroxide (66.6 ml of a 4M solution) and water (33 ml) were added. Theresulting 2-phase mixture was boiled and stirred under reflux for 1.75hours. Solvent (60 ml) was removed by distillation and the mixture wasallowed to cool to ambient temperature. The organic layer was separated,washed with water then evaporated under reduced pressure to give(+,−)-1-benzyl-3-hydroxymethyl-4-(4-fluoro-phenyl)-1,2,3,6-tetrahydropyridineas an oil (ee 5.4%)

Example 8

Triethylamine (1.39 ml) and benzenesulphonyl chloride (9.9 ml) wereadded to a solution of(−)-1-benzyl-3-hydroxymethyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine(19.8 g) made up to 100 g with toluene, with stirring under nitrogen.The mixture was stirred at ambient temperature for 72 hours. Water (64ml) was added and the mixture was stirred for 15 minutes. The organiclayer was separated, washed with water and a small sample of thesolution (5 ml) was removed. The remaining toluene solution was stirredwhile potassium acetate (7.18 g) and 4-methyl-2-pentanol (71 ml) wereadded. The mixture was then boiled and stirred under reflux with removalof water via a Dean & Stark apparatus for 5.5 hours. The mixture wasallowed to cool to ambient temperature and stood at this temperature for18 hours. Water (64 ml) was added and the mixture was stirred for 5minutes. The aqueous layer was separated off. The organic layer wasreturned to the reaction flask and stirred while water (51.2 ml)followed by concentrated hydrochloric acid (28.6 ml) were added. Thismixture was boiled under reflux for 1.5 hours. The reaction mixture wascooled to around 40° C. and the concentrated aqueous ammonia (22.1 ml)was added dropwise keeping the temperature below 45° C. Moreconcentrated aqueous ammonia solution (6 ml) was added to give a finalpH of 8-9. The reaction mixture was stirred for around 15 minutes andthen cooled to ambient temperature. The organic layer was separated,washed with water, dried and evaporated to give(+,−)-1-benzyl-3-hydroxymethyl-4-(4-fluoro-phenyl)-1,2,3,6-tetrahydropyridine(ee 4.4%)

Example 9

Triethylamine (12.9 ml) was added to a solution of(−)-1-benzyl-3-hydroxymethyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine(25.0 g) made up to 137 g with toluene, with stirring under nitrogen.The solution was cooled to 5° C. in an ice/water bath andmethanesulphonyl chloride (6.6 ml) was added dropwise over 20 minuteskeeping the temperature below 10° C. The mixture was stirred at 0-10° C.for 45 minutes. 4-Methyl-2-pentanol (6.5 ml) was added and the mixturestirred for a further 15 minutes. The mixture was allowed to warm to 20°C. and water (40 ml) was added. The mixture was stirred for 15 minutesand then the organic layer was separated, and washed with water (40 ml).The remaining toluene solution was stirred while potassium acetate (9.5g) and 4-methyl-2-pentanol (19.5 ml) were added. The mixture was thenboiled and stirred under reflux with removal of water via a Dean & Starkapparatus for 15 to 20 hours. The mixture was allowed to cool to 50° C.Water (40 ml) was added and the mixture was stirred for 15 minutes. Theaqueous layer was separated off. The organic layer was returned to thereaction flask and stirred while water (12.8 ml) followed byconcentrated hydrochloric acid (10.2 ml) were added. This mixture wasboiled under reflux for 3 hours. The reaction mixture was cooled toaround 40° C. and then concentrated aqueous ammonia (23 ml) was addeddropwise keeping the temperature below 45° C. to give a final pH of 8-9.The reaction mixture was stirred for around 15 minutes and then cooledto ambient temperature. The organic layer was separated, washed withwater (2×40 ml) and evaporated to give(+,−)-1-benzyl-3-hydroxymethyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine(ee 9.0%).

Example 10

Triethylamine (1.5 ml) was added to a solution of(+)-1-benzyl-3-hydroxymethyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine(2.82 g) in toluene (22.18 g) and the mixture was stirred at ambienttemperature. The solution was cooled to 5° C. in an ice/water bath andthe trifluoromethanesulphonic anhydride (1.8 ml) was added dropwise over5 minutes. The mixture was stirred at 0° C. to room temperature for 4hours, then stood for 48 hours. Water (25 ml) was added. The mixture wasstirred for 2 minutes and then ethyl acetate and 4M-NaOH were added todissolve an insoluble oil. The organic layer was separated, washed withwater (25 ml), and then dried, filtered and evaporated to give1-benzyl-4-(4-fluorophenyl)-1-azoniabicyclo[3.1.1]hept-3-enetrifluoro-methanesulphonate as an oil The oil was triturated with 60-80°C. petrol to give a solid.

Example 11

Potassium acetate (0.14 g) was added to a stirred solution of1-benzyl-4-(4-fluorophenyl)-1-azoniabicyclo[3.1.1]hept-3-enetrifluoromethanesulphonate (0.5 g) in toluene (2.5 ml) and propan-2-ol(2.5 ml). The mixture was then boiled and stirred under reflux for 24hours. The mixture was cooled to room temperature and toluene (10 ml)and water (5 ml) were added. The organic layer was separated, dried andevaporated to leave an oil. A solution of the oil in propan-2-ol (2 ml)and toluene (2 ml) was treated with 4M-NaOH (0.4 ml). The mixture wasboiled under reflux for 2 hours then cooled to room temperature. Water(5 ml) and toluene 95 ml) were added. The organic layer was separated,washed with water (2×5 ml) and evaporated to give(+,−)-1-benzyl-3-hydroxymethyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine(ee 5.48%).

1. A process for the racemisation of a compound of formula I comprisingthe steps of a) reacting an enantiomerically enriched compound offormula I

 in which R₁ represents an amine protecting group, with a compound offormula IIR₂X  II  in which R₂ represents a group of formula R₃SO₂—in which R₃represents optionally substituted phenyl, a C₁₋₆alkyl group or atrifluoromethyl group and X represents halo to give a compound offormula III

 in which i) R₂ represents a group of formula R₃SO₂—in which R₃represents optionally substituted phenyl, a C₁₋₆alkyl group or atrifluoromethyl group, b) reacting the compound of formula III with acompound of formula IV

 in which M represents an alkali metal and R represents H, a C₁₋₆alkylgroup, optionally substituted phenyl or an (optionally substitutedphenyl)hydroxyC₁₋₆alkyl group to give a substantially racemic compoundof formula V

 in which R₁ and R are as previously defined; and c) reacting thecompound of formula V with a hydrolysing agent to give a substantiallyracemic compound of formula I.
 2. A process for the racemisation of acompound of formula I comprising the steps of a) reacting anenantiomerically enriched compound of formula I

 in which R₁ represents an amine protecting group, with a compound offormula IIR₂X  II  in which R₂ represents a group of formula R₃SO₃—in which R₃represents optionally substituted phenyl, a C₁₋₆alkyl group or atrifluoromethyl group and X represents halo to give a compound offormula III

 in which i) R₂ represents a group of formula R₃SO₂—in which R₃represents optionally substituted phenyl, a C₁₋₈alkyl group or atrifluoromethyl group, wherein the compound of formula III is inequilibrium with a compound of formula IIIa

 in which R₁ represents an amine protecting group and R₂—is an anion ofR₂ b) reacting the compound of formula IIIa with a compound of formulaIV

 in which M represents an alkali metal and R represents H, a C₁₋₆alkylgroup, optionally substituted phenyl or an (optionally substitutedphenyl)hydroxyC₁₋₆alkyl group to give a substantially racemic compoundof formula V

 in which R₁ and R are as previously defined; and c) reacting thecompound of formula V with a hydrolysing agent to give a substantiallyracemic compound of formula I.
 3. A process according to claim 1 inwhich the amine protecting group is selected from a) allyl, b)benzhydryl, c) methoxymethyl, d) benzyloxymethyl, e) tetrahydropyranyl,f) an optionally substituted benzyl group, g) di(p-methoxyphenyl)methyl,h) triphenylmethyl, i) (p-methoxyphenyl)diphenylmethyl, j)diphenyl-4-pyridylmethyl, k) a C₁₋₆alkyl group, for example methyl orethyl, l) a trifluoro C₁₋₄alkyl group, m) an alkynyl group or n)p-methoxybenzyl.
 4. A process according to claim 1 in which R₃represents methyl or phenyl optionally substituted by a methyl, group, anitro group or halo.
 5. A process according to claim 1 in which thehydrolysing agent is selected from one or more of the following: aqueoussodium hydroxide, aqueous ammonia, aqueous potassium carbonate, aqueouspotassium bicarbonate, aqueous sodium bicarbonate, aqueous sodiumcarbonate, potassium hydroxide, aqueous potassium hydroxide and aqueouslithium hydroxide.
 6. A compound of formula IIIa

in which R₁ represents an amine protecting group and R₂ represents agroup of formula R₃SO₂—in which R₃ represents optionally substitutedphenyl, a C₁₋₆alkyl group or a trifluoromethyl group.
 7. A compoundaccording to claim 6 in which R₁ represents benzyl or a C₁₋₆ alkylgroup.